(+)-Subincanadine E and Determination of

Sep 27, 2017 - Total Synthesis of (±)/(+)-Subincanadine E and Determination of Absolute Configuration. Manojkumar G. Kalshetti and Narshinha P. Argad...
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Article Cite This: J. Org. Chem. 2017, 82, 11126-11133

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Total Synthesis of (±)/(+)-Subincanadine E and Determination of Absolute Configuration Manojkumar G. Kalshetti and Narshinha P. Argade* Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India S Supporting Information *

ABSTRACT: A facile synthesis of (±)-subincanadine E was described from tryptamine-based maleimide. 1,2-Addition of Grignard reagent to maleimide, internal activation of formed lactamol for in situ 1,4-addition of Grignard reagent, and associated position-specific allylic rearrangement in diastereoselective Pictet−Spengler cyclization were the key steps. Enantioselective first total synthesis of naturally occurring cytotoxic (+)-subincanadine E was also accomplished from (S)-acetoxysuccinimide via an unusual syn-addition of cuprate to the α,β-unsaturated lactam. Sinister absolute configuration was assigned to (+)-subincanadine E on the basis of total synthesis. (S)-Acetoxy group in the succinimide precursor was initially employed to impart regio- and stereoselectivity and then as a suitable leaving group to generate the desired conjugated lactam.

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INTRODUCTION The structurally interesting and biologically important cytotoxic alkaloids subincanadines A−G were isolated in 2−14 mg quantities from 100 g bark of the Brazilian medicinal plant Aspidosperma subincanum by Ohsaki and coworkers in 2002 (Figure 1).1,2 (+)-Subincanadine E is also named as pericine Figure 2. Biogenetic precursor (+)-subincanadine E (pericine) derived novel natural products.

activity and establishment of stereochemistry point of view. Retrosynthetically, corresponding tryptamine derived maleimide would be the potential precursor for total synthesis of (±)-subincanadine E (Scheme 1). Conceptually, the starting maleimide bears suitable functional groups for sequential 1,2and 1,4-addition of Grignard reagent followed by intramolecular Pictet−Spengler cyclization to provide the desired tetracyclic hexahydroindolizinoindolone. Condensation of the above stated well-protected lactam with acetaldehyde to generate the exocyclic carbon−carbon double bond and essential functional group interconversions delivers the known advanced diol intermediate, leading to the target compound. Moreover, (R)- and (S)-acetoxysuccinimides may also serve as appropriate starting materials for enantioselective synthesis of (+)- and (−)-subincanadines E. In continuation of our studies on the use of cyclic anhydrides to synthesize bioactive natural products,15−19 we herein report synthesis of (±)-subincanadine E and natural isomer (+)-subincanadine E from the readily available corresponding imides as starting materials (Schemes 1−5).

Figure 1. Potent cytotoxic alkaloids subincanadines A−G.1,11

and was first isolated from Picralima nitida by Stöckigt and coworkers in 1982.3,4 Recently, Kam and coworkers proposed that the (S)-pericine is a common biogenetic precursor of two structurally unprecedented monoterpenoid indole alkaloids (+)-arborisidine and (−)-arbornamine (Figure 2).5 (+)-Subincanadine E endures unique structural architecture and in vitro exhibits potent cytotoxicity against murine lymphoma L1210 cells (IC50, 0.3 μg/mL) and human epidermoid carcinoma KB cells (IC50, 4.4 μg/mL).1 A few new synthetic routes to the target compounds from Figure 1 have been reported in recent literature.6−14 Zhai and coworkers in 2014 reported the first total synthesis of (±)-subincanadine E.14 Development of new synthetic approaches for (+)/(−)-subincanadine E is essential from its exceptional structural features, promising biological © 2017 American Chemical Society

Received: August 22, 2017 Published: September 27, 2017 11126

DOI: 10.1021/acs.joc.7b02122 J. Org. Chem. 2017, 82, 11126−11133

Article

The Journal of Organic Chemistry Scheme 1. Concise Retrosynthetic Analysis of (±)-Subincanadine E

Scheme 2. Synthesis of (±)-Subincanadine E via Grignard Additions, Allylic Rearrangement, Pictet−Spengler Cyclization, Condensation and Ring Expansion Route

Scheme 3. Plausible Mechanisms for Couplings of Grignard Reagent with Maleimide and Intramolecular Cyclization Involving Position Specific Allylic Rearrangement

Scheme 4. Model Studies on Grignard Addition to Imides, Allylic Rearrangement, Isolation of the Proposed Diene Intermediate, and Intramolecular Cyclizations

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RESULTS AND DISCUSSION One-pot reaction of maleimide 1 with 4 equiv of allylmagnesium chloride at −78 °C followed by acidification with hydrochloric acid at 25 °C directly delivered the two allyl groups introduced and one of the double bond rearranged cyclized product (±)-9 in ∼20% yield (Scheme 2). Remarkably, two different types of coupling reactions of Grignard reagent with maleimide 1 and acid catalyzed diastereoselective intramolecular cyclization involving position-specific allylic rearrangement took place in one pot. Quenching of the

above-described Grignard reaction with saturated aqueous ammonium chloride to obtain the intermediate product (±)-4 and its immediate reaction with 2 N HCl provided the desired product (±)-9 in 55% yield. The plausible mechanisms for reactions of Grignard reagent with maleimide and acid catalyzed intramolecular Pictet−Spengler cyclization involving position-specific allylic rearrangement are depicted in Scheme 3. On the basis of control experiments described in Scheme 4, the 1,2-addition of Grignard reagent to maleimide 1 takes place first and forms the magnesium complex 2, which internally 11127

DOI: 10.1021/acs.joc.7b02122 J. Org. Chem. 2017, 82, 11126−11133

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Scheme 5. Enantioselective Synthesis (+)-Subincanadine E from (S)-Acetoxysuccinimide via an Unanticipated syn-Addition of the Cuprate

activates lactam moiety for in situ 1,4-addition of Grignard reagent and delivers the lactamol 4.20 Lactamol 4 on treatment with 2 N HCl underwent amide nitrogen driven dehydration to form the diene intermediate 7 which, on selective rearrangement of the double bond followed by diastereoselective intramolecular cyclization directly resulted in the essential product (±)-9. The in situ allylic rearrangement was eventually useful to appropriately tailor the carbon chain at an angular position. Mechanistically above-mentioned intramolecular Pictet−Spengler cyclization takes place via flat iminium ion intermediate and the incoming nucleophile approaches from less hindered side in the favored intermediate 8b, resulting in syn-product (±)-9.7,21 Reaction of maleimide 1 with 2.20 equiv of allylmagnesium chloride at −78 °C exclusively formed the lactomol intermediate 19 (Scheme 4). The sensitive lactamol 19 on immediately performed acid induced intramolecular cyclization furnished the corresponding α,β-unsaturated indolizinoindolone 20 in 85% yield without an allylic rearrangement. The indolizinoindolone 20 did not undergo 1,4-addition of Grignard reagent in absence of CuBr due to the lack of substrate/reagent activation. The witnessed in situ allylic rearrangement was specific to the succinimide derived lactamols, and it was feasible to isolate an exclusively formed diene intermediate 2422 in the model transformation of succinimide 22 to indolizinoindolone 25. The exclusive formation of relatively more stable diene (E)-24 could be attributed to the effective conjugation of a lone pair on the nitrogen atom. Direct transformation of two different types of carbon− carbon double bonds in compound (±)-9 via dihydroxylation, oxidative cleavage, and reduction to the corresponding product (±)-diol 12 was low yielding. The stepwise transformations of terminal and internal olefins in compound (±)-9 initially provided primary alcohol (±)-11 in 93% yield and then the desired (±)-diol 12 in 87% yield (Scheme 2). The structure of advanced intermediate (±)-diol 12 was unambiguously established by X-ray crystallographic data, which also confirmed the formation of syn-product (±)-9 in the above-mentioned Pictet−Spengler cyclization. Boc-protection of indole nitrogen atom and two primary alcohol units in compound (±)-12 provided the required product (±)-13 in quantitative yield. Condensation of (±)-lactam 13 with acetaldehyde followed by mesylation of the formed alcohol and stereoselective elimination of mesylate delivered the column chromatographically separable mixture of α,β-unsaturated lactam (±)-15a as a major product in 88% yield and (±)-15b as a minor product in 7% yield over three steps. As expected, the vinylic proton of a major E-isomer (±)-15a was more

deshielded (6.56 ppm) compared to the corresponding minor Z-isomer (±)-15b (5.82 ppm) due to the five membered periintraction with a γ-lactam carbonyl. Alane reduction of a lactam carbonyl in compound (±)-15 to (±)-amine 16 in 92% yield followed by trifluoroacetic acid induced deprotection of three Boc-groups furnished the known (±)-diol 17 in 96% yield. A one-pot three-step transformation of (±)-diol 17 under Zhai and coworkers’ conditions14 delivered the desired (±)-subincanadine E (18) in 60% yield. The analytical and spectral data obtained for (±)-diol 17 and (±)-subincanadine E (18) were in complete agreement with the reported data.1,14 Finally, we planned the enantioselective synthesis of (+)/(−)-subincanadine E (18) from (S)-acetoxysuccinimide 2623 (Scheme 5). As expected, Grignard reagent regioselectively attacked on the more reactive imide carbonyl of (S)acetoxysuccinimide 26 and directly delivered the corresponding deacylated single diastereomer (−)-27 in 89% yield. Acidcatalyzed Pictet−Spengler cyclization of (−)-hydroxy-lactamol 27 was not diastereoselective and provided nearly 1:1 mixture of the corresponding diastereomers in 73% yield.24 (−)-Hydroxy-lactamol 27 on treatment with pivaloyl chloride and triethylamine selectively formed the corresponding sterically hindered lactamol intermediate 28 in quantitative yield, which was used for the next step without purification and characterization for stability issues. Acid-catalyzed Pictet−Spengler cyclization of lactamol 28 was stereoselective and exclusively provided the expected double bond rearranged cyclized synproduct (−)-29 in 75% yield. The structure of product (−)-29 was also established by X-ray crystallographic data and confirmed the syn-relationship between the angular alkenyl chain and O-pivaloyl group. Base-induced elimination of pivaloyl group in compound (−)-29 resulted in the α,βunsaturated lactam 30 in 90% yield. The addition of allylcuprate to (−)-lactam 30 was highly diastereoselective but unexpectedly resulted in the syn-product (−)-9 in 83% yield with >99% de/ee (by 1H NMR/HPLC). The analytical and spectral data obtained for syn-product (−)-9 were in complete agreement with the earlier obtained data for syn-product (±)-9 from Scheme 2. Such type of syn-addition precedence is known in the literature; however, genesis of stereoselection still remains an unanswered question.25,26 The syn-product (−)-9 was transformed to (+)-diol 17 in 62% overall yield by repeating 8 steps from Scheme 2. One-pot three-step transformation of (+)-diol 17 under Zhai and coworkers conditions14 delivered the desired (+)-subincanadine E (18) in 59% yield. The analytical and spectral data obtained for (+)-subincanadine E (18) were in complete agreement with the reported data,1,14 including specific rotations {natural1 [α]23D +39.0 (c 1.0 MeOH), synthetic 18 [α]25D +42.3 (c 0.12 11128

DOI: 10.1021/acs.joc.7b02122 J. Org. Chem. 2017, 82, 11126−11133

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The Journal of Organic Chemistry MeOH)}. Enantioselective first total synthesis of (+)-subincanadine E (18) was accomplished from (S)-acetoxysuccinimide 26 with 18% overall yield, and Sinister configuration was assigned to the natural product.

h. The reaction was quenched with saturated aqueous NH4Cl solution at 0 °C. The reaction mixture was concentrated in vacuo, and the obtained residue was dissolved in EtOAc (50 mL). The organic layer was washed with water and brine and dried over Na2SO4. Concentration of organic layer in vacuo afforded lactamol 19, which was directly used for the next step. To a stirred solution of lactamol 19 in THF (10 mL) was added 2 N HCl (0.30 mL) at 0 °C, and the reaction mixture was stirred for 5 h and allowed to reach 25 °C. The reaction was quenched with saturated aqueous NaHCO3 at 0 °C, and the reaction mixture was extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, PE−EtOAc, 50:50) afforded compound (±)-20 as a yellow solid (280 mg, 85%). Mp 191−193 °C; 1H NMR (CDCl3, 400 MHz) δ 2.70−2.96 (m, 4H), 3.32 (td, J = 12.5 and 5.5 Hz, 1H), 4.62 (dd, J = 13.4 and 6.1 Hz, 1H), 5.12−5.22 (m, 2H), 5.64−5.77 (m, 1H), 6.21 (d, J = 6.1 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 5.5 Hz, 1H), 7.36 (d, J = 6.1 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 8.47 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.8, 35.9, 41.9, 67.0, 107.9, 111.1, 118.8, 119.8, 119.9, 122.4, 126.5, 126.8, 131.0, 132.9, 136.3, 150.1, 171.6; ESIMS (m/z) 265 [M + H]+; HRMS (ESI) calcd for C17H17N2O 265.1335, found 265.1337; IR (CHCl3) νmax 3459, 1678 cm−1. (E)-1-[2-(1H-Indol-3-yl)ethyl]-5-allylidenepyrrolidin-2-one (24). To a stirred solution of compound 2227 (500 mg, 2.10 mmol) in dry THF (15 mL) was added a solution of allylmagnesium chloride in THF (2 M, 2.10 mL, 4.20 mmol) in a dropwise mode at −78 °C under argon atmosphere. The reaction mixture was stirred for 1.5 h at the same temperature and then allowed to reach 0 °C over the next 1.5 h. The reaction was quenched with saturated aqueous NH4Cl solution. The reaction mixture was concentrated in vacuo, and the obtained residue was dissolved in EtOAc (50 mL). The organic layer was washed with water and brine and dried over Na2SO4. The concentration of organic layer in vacuo afforded lactamol 23, which was directly used for the next step. To a stirred solution of lactamol 23 in THF (12 mL) was added 2 N HCl (0.50 mL) at 0 °C, and the reaction mixture was stirred for 20 min. The reaction was quenched with saturated aqueous NaHCO3 at 0 °C, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, PE−EtOAc, 50:50) afforded compound 24 as a white solid (428 mg, 78%). Mp 105−107 °C; 1H NMR (CDCl3, 200 MHz) δ 2.40−2.60 (m, 2H), 2.70−2.90 (m, 2H), 3.04 (t, J = 8.2 Hz, 2H), 3.83 (t, J = 7.7 Hz, 2H), 4.98 (d, J = 10.2 Hz, 1H), 5.08 (d, J = 16.8 Hz, 1H), 5.60 (d, J = 11.0 Hz, 1H), 6.30−6.55 (m, 1H), 7.08 (d, J = 2.2 Hz, 1H), 7.05−7.30 (m, 2H), 7.36 (d, J = 7.1 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 8.23 (s, 1H); 13 C NMR (CDCl3, 50 MHz) δ 21.7, 22.5, 28.6, 40.7, 102.6, 111.2, 112.5, 112.8, 118.5, 119.4, 121.96, 122.00, 127.4, 131.6, 136.2, 142.5, 175.7; ESIMS (m/z) 289 [M + Na]+; HRMS (ESI) calcd for C17H18N2ONa 289.1311, found 289.1314; IR (CHCl3) νmax 3423, 1681, 1601 cm−1. (E)-11b-(Prop-1-en-1-yl)-1,2,5,6,11,11b-hexahydro-3H-indolizino(8,7-b)indol-3-one (25). To a stirred solution of compound 24 (400 mg, 1.50 mmol) in THF (10 mL) was added 2 N HCl (0.50 mL) at 0 °C, and the reaction mixture was stirred for 3 h and allowed to reach 25 °C. The reaction was quenched with saturated aqueous NaHCO3 at 0 °C, and the reaction mixture was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, PE−EtOAc, 40:60) afforded compound 25 as a white solid (328 mg, 82%). Mp 177−179 °C; 1H NMR (CDCl3, 500 MHz) δ 1.70 (d, J = 6.8 Hz, 3H), 2.25 (q, J = 10.9 Hz, 1H), 2.39−2.51 (m, 2H), 2.69 (dt, J = 17.4 and 9.5 Hz, 1H), 5.80 (dd, J = 15.4 and 5.2 Hz, 1H), 2.85−2.94 (m, 1H), 3.09 (td, J = 16.9 and 5.5 Hz, 1H), 4.44 (dd, J = 13.1 and 6.1 Hz, 1H), 5.42 (qd, J = 15.4 and 6.4 Hz, 1H), 5.70 (d, J = 15.3 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H),

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CONCLUSION In summary, from the readily available maleimide/succinimide, we described a new efficient approach to (±)/(+)-subincanadine E and established its absolute configuration. The 1,4addition of Grignard reagent to the internally activated lactamol, witnessed position selective allylic rearrangements in succinimide derived lactamols, and stereoselective syn-addition of cuprate to the unsaturated lactam are noteworthy. Our present synthetic strategy is flexible and paves efficient enantioselective routes to subincanadines A−G and focused mini-library of their unnatural congeners and derivatives for structure−activity relationship studies.

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EXPERIMENTAL SECTION

General Description. Melting points are uncorrected. The 1H NMR spectra were recorded on 200, 400, and 500 MHz NMR spectrometers using solvent residue signal as an internal standard [1H NMR: CDCl3 (7.27), CD3OD (3.31), DMSO-d6 (2.50); 13C NMR: CDCl3 (77.00), CD3OD (49.00), DMSO-d6 (39.51)]. The 13C NMR spectra were recorded on 200 NMR (50 MHz), 400 NMR (100 MHz), and 500 NMR (125 MHz) spectrometers. HRMS (ESI) were taken on an Orbitrap (quadrupole plus ion trap) and TOF mass analyzer. The IR spectra were recorded on an FT-IR spectrometer. Column chromatographic separations were carried out on silica gel (60−120 mesh and 230−400 mesh). Commercially available starting materials and reagents were used. 1-Allyl-11b-[(E)-prop-1-en-1-yl]-1,2,5,6,11,11b-hexahydro-3Hindolizino(8,7-b)indol-3-one (9). To a stirred solution of compound 127 (2.00 g, 8.33 mmol) in dry THF (40 mL) was added solution of allylmagnesium chloride in THF (2 M, 16.06 mL, 33.33 mmol) in a dropwise mode at −78 °C under argon atmosphere. The reaction mixture was stirred for 1 h at the same temperature and then allowed to reach 25 °C. It was further stirred for 4 h, and the reaction was quenched with saturated aqueous NH4Cl solution at 0 °C. The reaction mixture was concentrated in vacuo, and the obtained residue was dissolved in EtOAc (80 mL). The organic layer was washed with water and brine and dried over Na2SO4. The concentration of organic layer in vacuo afforded lactamol 4, which was directly used for the next step. To a stirred solution of lactamol 4 in THF (25 mL) was added 2 N HCl (1.50 mL) at 0 °C, and the reaction mixture was stirred for 6 h and allowed to reach 25 °C. The reaction was quenched with saturated aqueous NaHCO3 at 0 °C, and the aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, EtOAc−PE, 30:70) afforded single diastereomer (±)-9 as a yellow solid (1.40 g, 55%). Mp 83−85 °C; 1H NMR (CDCl3, 400 MHz) δ 1.73 (d, J = 6.1 Hz, 3H), 2.27−2.48 (m, 2H), 2.48−2.63 (m, 3H), 2.75−3.00 (m, 3H), 4.46 (dd, J = 12.2 and 4.9 Hz, 1H), 5.24−5.33 (m, 2H), 5.35−5.45 (m, 1H), 5.61 (d, J = 15.9 Hz, 1H), 5.87−6.00 (m, 1H), 7.13 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 8.18 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.7, 21.4, 34.8, 35.3, 37.1, 44.4, 65.9, 108.6, 111.0, 117.7, 118.5, 119.8, 122.2, 126.4, 127.5, 129.0, 134.6, 135.8, 137.1, 171.6; ESIMS (m/z) 307 [M + H]+; HRMS (ESI) calcd for C20H23N2O 307.1805, found 307.1802; IR (CHCl3) νmax 3284, 1681 cm−1. 11b-Allyl-1,2,5,6,11,11b-hexahydro-3H-indolizino(8,7-b)indol-3one (20). To a stirred solution of compound 127 (300 mg, 1.25 mmol) in dry THF (10 mL) was added a solution of allylmagnesium chloride in THF (2 M, 1.37 mL, 2.75 mmol) in a dropwise mode at −78 °C under argon atmosphere. The reaction mixture was stirred for 1.5 h at the same temperature and then allowed to reach 0 °C over the next 1.5 11129

DOI: 10.1021/acs.joc.7b02122 J. Org. Chem. 2017, 82, 11126−11133

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The Journal of Organic Chemistry

a white solid (972 mg, 90%). Mp 211−213 °C; [α]25D −298.4 (c 0.2 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.69 (d, J = 6.1 Hz, 3H), 2.80 (dd, J = 15.5 and 5.5 Hz, 1H), 2.86−2.99 (m, 1H), 3.24 (td, J = 12.2 and 4.3 Hz, 1H), 4.54 (dd, J = 13.1 and 6.7 Hz, 1H), 5.46 (d, J = 15.2 Hz, 1H), 5.51−5.62 (m, 1H), 6.18 (d, J = 6.1 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 6.1 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 8.64 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.7, 21.9, 35.1, 68.2, 109.2, 111.0, 118.8, 119.8, 122.5, 126.4, 126.5, 128.6, 130.6, 131.1, 136.3, 149.7, 170.8 ; ESIMS (m/z) 265 [M + H]+; HRMS (ESI) calcd for C17H17N2O 265.1335, found 265.1337; IR (CHCl3) νmax 3462, 1677 cm−1. (−)-(1S,11bR)-1-Allyl-11b-[(E)-prop-1-en-1-yl]-1,2,5,6,11,11b-hexahydro-3H-indolizino(8,7-b)indol-3-one (9). To a stirred solution of compound (−)-30 (900 mg, 3.40 mmol) in dry THF (25 mL) containing CuBr (48 mg, 0.34 mmol) was added a solution of allylmagnesium chloride (2 M in THF, 5.10 mL, 10.22 mmol) in a dropwise mode at −78 °C under argon atmosphere. The reaction mixture was allowed to reach 0 °C in 3 h, and the reaction was quenched with saturated aqueous NH4Cl solution. The reaction mixture was concentrated in vacuo, and the obtained residue was dissolved in EtOAc (40 mL). The organic layer was washed with water and brine and dried over Na2SO4. The concentration of organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, EtOAc−PE, 30:70) afforded compound (−)-9 as a white solid (865 mg, 83%). Mp 83− 85 °C; [α]25D −87.0 (c 0.22 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.73 (d, J = 6.1 Hz, 3H), 2.27−2.48 (m, 2H), 2.48−2.63 (m, 3H), 2.75−3.00 (m, 3H), 4.46 (dd, J = 12.2 and 4.9 Hz, 1H), 5.24−5.33 (m, 2H), 5.35−5.45 (m, 1H), 5.61 (d, J = 15.9 Hz, 1H), 5.87−6.00 (m, 1H), 7.13 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 8.18 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 17.7, 21.4, 34.8, 35.3, 37.1, 44.4, 65.9, 108.6, 111.0, 117.7, 118.5, 119.8, 122.2, 126.4, 127.5, 129.0, 134.6, 135.8, 137.1, 171.6; ESIMS (m/z) 307 [M + H]+; HRMS (ESI) calcd for C20H23N2O 307.1805, found 307.1802; IR (CHCl3) νmax 3284, 1681 cm−1. (−)-2-{(1R,11bS)-3-Oxo-11b-[(E)-prop-1-en-1-yl]-2,3,5,6,11,11bhexahydro-1H-indolizino(8,7-b)indol-1-yl}acetaldehyde (10). To a stirred solution of compound (−)-9 (800 mg, 2.61 mmol) in THF:H2O (3:1, 25 mL) was added NMO (50% in water, 3.05 mL, 13.07 mmol) and catalytic amount of OsO4 (0.20 mL, 0.5 M solution in t-BuOH) at 25 °C, and the reaction mixture was stirred for 24 h. The reaction was quenched with saturated solution of Na2S2O3 and further stirred for 30 min. Aqueous layer was extracted in EtOAc (3 × 30 mL), and the combined organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo, and the obtained diol was directly used for the next step. To a stirred solution of obtained diol in THF:H2O (1:1, 30 mL) was added NaIO4 (1.25 g, 5.88 mmol) at 25 °C in three equal lots, and the reaction was monitored on TLC. The reaction mixture diluted with EtOAc (50 mL) after 1.5 h, and the organic layer was washed with brine and dried over Na2SO4. The concentration of organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, EtOAc−PE, 40:60) afforded compound (−)-10 as a solid (764 mg, 95%). Mp 97−99 °C; [α]25D −94.2 (c 0.1 CHCl3); 1 H NMR (CDCl3, 500 MHz) δ 1.70 (d, J = 6.1 Hz, 3H), 2.25 (dd, J = 16.8 and 9.5 Hz, 1H), 2.67−2.98 (m, 4H), 2.98−3.20 (m, 3H), 4.44 (dd, J = 12.8 and 5.7 Hz, 1H), 5.38−5.50 (m, 2H), 7.12 (t, J = 7.3 Hz, 1H), 7.21 (t, J = 7.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 9.67 (s, 1H), 9.83 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 17.6, 21.0, 35.5, 36.2, 37.2, 47.2, 66.1, 108.3, 111.4, 118.4, 119.6, 122.2, 126.4, 128.4, 130.0, 135.1, 136.0, 171.0, 202.0; ESIMS (m/z) 309 [M + H]+; HRMS (ESI) calcd for C19H21N2O2 309.1598, found 309.1590; IR (CHCl3) νmax 3376, 3020, 1725, 1677, 1601 cm−1. (−)-(1S,11bR)-1-(2-Hydroxyethyl)-11b-[(E)-prop-1-en-1-yl]1,2,5,6,11,11b-hexahydro-3H-indolizino(8,7-b)indol-3-one (11). To a stirred solution of aldehyde (−)-10 (740 mg, 2.40 mmol) in MeOH (15 mL) was added NaBH4 (133 mg, 3.60 mmol) at 0 °C in 2 equal lots, and the reaction mixture was stirred for 30 min. The reaction was quenched with aqueous NH4Cl, and the reaction mixture was concentrated in vacuo. The obtained residue was dissolved in

7.36 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 8.63 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 17.4, 21.1, 30.4, 32.1, 34.9, 63.3, 108.0, 111.0, 118.4, 119.6, 122.0, 126.5, 127.3, 131.2, 134.9, 136.2, 173.2; ESIMS (m/z) 267 [M + H]+; HRMS (ESI) calcd for C17H19N2O 267.1492, found 267.1494; IR (CHCl3) νmax 3419, 1677 cm−1. (−)-(4S)-1-[2-(1H-Indol-3-yl)ethyl]-5-allyl-4,5-dihydroxypyrrolidin-2-one (27). To a stirred solution of compound (−)-2623 (2.00 g, 6.66 mmol) in dry THF (30 mL) was added a solution of allylmagnesium chloride in THF (2 M, 13.33 mL, 26.66 mmol) in a dropwise mode at −78 °C under argon atmosphere. The reaction mixture was allowed to reach 0 °C over the next 3 h and then quenched with saturated aqueous NH4Cl solution. The reaction mixture was concentrated in vacuo, and the obtained residue was dissolved in EtOAc (80 mL). The organic layer was washed with brine and dried over Na2SO4. The concentration of organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 230−400 mesh, MeOH−DCM, 2:98) afforded compound (−)-27 as foam (1.70 g, 89%). [α]25D −18.7 (c 0.2 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 2.33−2.44 (m, 2H), 2.55 (dd, J = 14.6 and 7.3 Hz, 1H), 2.69 (dd, J = 17.7 and 6.7 Hz, 1H), 3.00 (d, J = 4.9 Hz, 1H), 3.03−3.12 (m, 1H), 3.13−3.22 (m, 1H), 3.33− 3.44 (m, 1H), 3.61 (s, 1H), 3.66−3.77 (m, 1H), 4.16 (br s, 1H), 5.07− 5.20 (m, 2H), 5.58−5.74 (m, 1H), 7.04 (s, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 8.08 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 24.7, 39.0, 40.3, 41.3, 68.8, 91.0, 111.3, 113.1, 118.9, 119.4, 120.1, 122.0, 122.2, 127.3, 131.3, 136.2, 172.4; ESIMS (m/z) 323 [M + Na]+; HRMS (ESI) calcd for C17H20N2O3Na 323.1366, found 323.1363; IR (CHCl3) νmax 3619, 3478, 3352, 1678 cm−1. (−)-(1S,11bR)-3-Oxo-11b-[(E)-prop-1-en-1-yl]-2,3,5,6,11,11b-hexahydro-1H-indolizino(8,7-b)indol-1-yl Pivalate (29). To a stirred solution of lactamol (−)-27 (1.70 g, 5.66 mmol) in CH2Cl2 (25 mL) were slowly added Et3N (1.93 mL, 14.16 mmol) and pivCl (1.10 mL, 8.49 mmol) at 0 °C. The reaction mixture was stirred for 3 h and allowed to reach 25 °C, and the reaction was quenched with water. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and the combined organic layer was washed with aqueous NaHCO3 and brine and dried over Na2SO4. The organic layer was concentrated in vacuo, and the obtained vacuum-dried O-pivaloyl lactamol 28 was directly used for the next step. To a stirred solution of lactamol 28 in THF (20 mL) was added 2 N HCl (2.00 mL) at 0 °C, and the reaction mixture was stirred for 36 h and allowed to reach 25 °C. The reaction was quenched with saturated aqueous NaHCO3 at 0 °C, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, EtOAc− PE, 20:80) afforded single diastereomer (−)-29 as a solid (1.50 g, 75%). Mp 171−173 °C; [α]25D −59.3 (c 0.25 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.30 (s, 9H), 1.67 (d, J = 7.3 Hz, 3H), 2.73 (dd, J = 15.2 and 4.9 Hz, 1H), 2.82−2.99 (m, 3H), 3.06 (td, J = 12.2 and 4.9 Hz, 1H), 4.45 (dd, J = 12.8 and 6.1 Hz, 1H), 5.30−5.45 (m, 2H), 5.52 (d, J = 15.9 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 9.57 (s, 1H); 13 C NMR (CDCl3, 100 MHz) δ 17.7, 20.7, 27.2, 35.2, 36.5, 39.0, 68.3, 73.2, 109.3, 111.5, 118.3, 119.5, 122.3, 126.3, 127.8, 131.4, 132.8, 135.7, 169.3, 179.6; ESIMS (m/z) 367 [M + H]+; HRMS (ESI) calcd for C22H27N2O3 367.2016, found 367.2011; IR (CHCl3) νmax 3390, 1684, 1612 cm−1. (−)-(S,E)-11b-(Prop-1-en-1-yl)-5,6,11,11b-tetrahydro-3Hindolizino(8,7-b)indol-3-one (30). To a stirred suspension of NaH (410 mg, 10.24 mmol) in dry THF (25 mL) was slowly added the solution of compound (−)-29 (1.50 g, 4.098 mmol) in THF (10 mL) in dropwise mode at 25 °C. The reaction was monitored by TLC and quenched with aqueous NH4Cl after 10 min. The reaction mixture was concentrated in vacuo, and the obtained residue was dissolved in EtOAc (50 mL). The organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, PE−EtOAc, 50:50) afforded compound (−)-30 as 11130

DOI: 10.1021/acs.joc.7b02122 J. Org. Chem. 2017, 82, 11126−11133

Article

The Journal of Organic Chemistry

4.11−4.20 (m, 1H), 4.44 (dd, J = 13.7 and 7.3 Hz, 1H), 4.90 (d, J = 12.2 Hz, 1H), 5.12 (d, J = 12.2 Hz, 1H), 7.24 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H); 13 C NMR (CDCl3, 100 MHz) δ 21.0, 27.6, 27.7, 28.2, 31.2, 34.5, 37.5, 37.6, 66.0, 66.1, 67.7, 81.9, 82.3, 84.8, 115.6, 118.6, 119.0, 122.9, 125.3, 128.4, 135.0, 136.0, 150.4, 153.2, 153.6, 173.8; ESIMS (m/z) 601 [M + H]+; HRMS (ESI) calcd for C32H45N2O9 601.3120, found 601.3113; IR (CHCl3) νmax 1738, 1678, 1600 cm−1. (−)-tert-Butyl (1S,11bS)-1-{2-[(tert-Butoxycarbonyl)oxy]ethyl}11b-{[(tert-butoxycarbonyl) oxy]methyl}-2-(1-hydroxyethyl)-3-oxo1,2,3,5,6,11b-hexahydro-11H-indolizino(8,7-b)indole-11-carboxylate (14). Freshly prepared solution of LDA in THF (1 M, 0.50 mL, 0.50 mmol) was added to a stirred solution of compound (−)-13 (200 mg, 0.33 mmol) in THF (10 mL) in a dropwise mode at −78 °C under argon atmosphere. The reaction mixture was stirred for 1 h at −78 °C, and solution of acetaldehyde (75 μL, 1.33 mmol) in THF (3 mL) was slowly added to the reaction mixture. The reaction was quenched after 2 h by using aqueous NH4Cl, and the reaction mixture was concentrated in vacuo. The obtained residue was dissolved in EtOAc (50 mL), and the organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, EtOAc−PE, 30:70) afforded compound (−)-14 as a solid (210 mg, 98%). Mp 63−65 °C; [α]25D −111.4 (c 0.3 CHCl3); 1H NMR (CDCl3, 500 MHz) δ 0.98 (d, J = 6.1 Hz, 3H), 1.37 (s, 9H), 1.40 (s, 1H), 1.47 (s, 9H), 1.73 (s, 9H), 1.92 (sept, J = 6.9 Hz, 1H), 2.37 (dd, J = 8.2 and 3.4 Hz, 1H), 2.55−2.72 (m, 3H), 2.90−3.00 (m, 1H), 3.44 (sext, J = 5.7 Hz, 2H), 3.71 (s, 1H), 4.05−4.15 (m, 1H), 4.18−4.25 (m, 1H), 4.44 (dd, J = 13.3 and 6.9 Hz, 1H), 4.93 (d, J = 5.0 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 20.1, 20.5, 27.6, 27.8, 28.3, 30.4, 35.3, 39.6, 53.9, 65.4, 66.5, 66.9, 68.7, 81.9, 82.3, 85.0, 116.0, 118.2, 118.5, 123.0, 125.2, 128.5, 134.8, 135.6, 150.2, 153.0, 153.5, 176.6; ESIMS (m/z) 645 [M + H]+; HRMS (ESI) calcd for C34H49N2O10 645.3382, found 645.3365; IR (CHCl3) νmax 3556, 1736, 1667 cm−1. (−)-tert-Butyl (1S,11bS,E/Z)-1-{2-[(tert-Butoxycarbonyl)oxy]ethyl}-11b-{[(tert-butoxycarbonyl)oxy]methyl}-2-ethylidene-3-oxo1,2,3,5,6,11b-hexahydro-11H-indolizino(8,7-b)indole-11-carboxylate (15a/b). To a stirred solution of alcohol (−)-14 (150 mg, 0.232 mmol) in CH2Cl2 (8 mL) was slowly added Et3N (95 μL, 0.697 mmol) and MsCl (26 μL, 0.348 mmol) at 0 °C. The reaction mixture was stirred for 3 h and allowed to reach 25 °C. The reaction was quenched with water, and the aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic layer was washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The obtained mesylate was directly used for the next step without any purification. To a stirred suspension of NaH (20 mg, 0.498 mmol) in dry THF (10 mL) was slowly added the solution of Omesylate in THF (5 mL) in dropwise mode at 25 °C. The reaction was quenched with aqueous NH4Cl after 30 min, and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 230−400 mesh, EtOAc−PE, 20:80) afforded compound (−)-15b as a solid (10 mg, 6.86%) and (−)-15a as a solid (128 mg, 87.79%). 15a: Mp 77−79 °C; [α]25D −124.3 (c 0.2 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.28 (s, 9H), 1.48 (s, 9H), 1.70 (d, J = 6.7 Hz, 3H), 1.75 (s, 9H), 1.88−1.98 (m, 1H), 2.37−2.50 (m, 1H), 2.61 (dd, J = 16.5 and 5.5 Hz, 1H), 2.99 (ddd, J = 11.3, 10.7, and 6.7 Hz, 1H), 3.59 (td, J = 12.2 and 5.5 Hz, 1H), 3.78 (dd, J = 10.1 and 4.9 Hz, 1H), 3.97 (q, J = 8.0 Hz, 1H), 4.15−4.24 (m, 1H), 4.45 (dd, J = 13.4 and 7.3 Hz, 1H), 4.80 (d, J = 11.6 Hz, 1H), 5.22 (d, J = 11.6 Hz, 1H), 6.56 (q, J = 7.3 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.7, 19.8, 27.4, 27.7, 28.2, 29.1, 36.0, 39.3, 64.7, 65.5, 67.6, 81.6, 82.0, 84.6, 115.9, 118.3, 118.8, 122.7, 124.8, 128.7, 131.1, 134.0, 134.3, 135.5, 150.2, 152.9, 153.5, 170.9; ESIMS (m/z) 627 [M + H]+; HRMS (ESI)

EtOAc (40 mL), and the organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 230−400 mesh, DCM−MeOH, 2:98) afforded compound (−)-11 as a solid (739 mg, 98%). Mp 110−112 °C; [α]25D −212.1 (c 0.13 CHCl3); 1H NMR (CD3OD, 500 MHz) δ 1.65−1.80 (m, 1H), 1.73 (d, J = 5.4 Hz, 3H), 2.25−2.35 (m, 1H), 2.39 (dd, J = 15.1 and 11.9 Hz, 1H), 2.45−2.55 (m, 1H), 2.59 (dd, J = 15.3 and 7.7 Hz, 1H), 2.70−2.83 (m, 2H), 2.96 (td, J = 11.6 and 5.8 Hz, 1H), 3.55−3.65 (m, 1H), 3.65−3.75 (m, 1H), 4.30−4.37 (m, 1H), 5.31−5.40 (m, 1H), 5.72 (d, J = 16.0 Hz, 1H), 7.00 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.3 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H); 13C NMR (CD3OD, 125 MHz) δ 17.8, 22.4, 34.1, 36.2, 37.7, 43.9, 61.5, 68.0, 108.2, 112.3, 119.0, 120.1, 122.7, 127.7, 129.0, 129.6, 136.2, 138.2, 174.7; ESIMS (m/z) 311 [M + H]+; HRMS (ESI) calcd for C19H23N2O2 311.1754, found 311.1749; IR (CHCl3) νmax 3333, 1666 cm−1. (+)-(1S,11bS)-1-(2-Hydroxyethyl)-11b-(hydroxymethyl)1,2,5,6,11,11b-hexahydro-3H-indolizino(8,7-b)indol-3-one (12). To a stirred solution of compound (−)-11 (700 mg, 2.25 mmol) in THF:H2O (3:1, 25 mL) was added NMO (50% in water, 2.60 mL, 11.29 mmol) and a catalytic amount of OsO4 (0.15 mL, 0.50 M solution in t-BuOH) at 25 °C, and the reaction mixture was stirred for 72 h. The reaction was quenched with saturated solution of Na2S2O3 and further stirred for 30 min. Aqueous layer was extracted with EtOAc (3 × 40 mL), and the combined organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo, and the obtained vacuum-dried triol was directly used for the next step. To a stirred solution of obtained triol in THF:H2O (1:1, 35 mL) was added NaIO4 (2.10 g, 10.17 mmol) at 25 °C in 3 equal lots. The reaction mixture was diluted with EtOAc (60 mL) after 1.5 h, and the organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The obtained aldehyde was immediately used for the next reaction without any purification. To a stirred solution of aldehyde in MeOH (15 mL) was added the NaBH4 (171 mg, 4.63 mmol) at 0 °C. The reaction was quenched with aqueous NH4Cl after 30 min, and the reaction mixture was concentrated in vacuo. The obtained residue was dissolved in EtOAc (50 mL), and the organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 230−400 mesh, MeOH−DCM, 7:93) afforded compound (+)-12 as a solid (589 mg, 87%). Mp 117−119 °C; [α]25D +382.6 (c 0.21 MeOH); 1H NMR (DMSO-d6, 400 MHz) δ 1.80−1.95 (m, 1H), 2.22−2.47 (m, 4H), 2.52−2.65 (m, 1H), 2.74 (dd, J = 15.3 and 4.9 Hz, 1H), 3.05 (td, J = 12.5 and 4.9 Hz, 1H), 3.37−3.47 (m, 1H), 3.50−3.60 (m, 1H), 3.69 (dd, J = 11.6 and 4.9 Hz, 1H), 3.85 (dd, J = 11.6 and 6.1 Hz, 1H), 4.28 (dd, J = 12.8 and 6.1 Hz, 1H), 4.58 (t, J = 5.5 Hz, 1H), 5.16 (t, J = 5.5 Hz, 1H), 6.98 (t, J = 7.3 Hz, 1H), 7.07 (t, J = 7.3 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 10.82 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 21.3, 31.8, 34.6, 37.6, 40.9, 59.7, 62.4, 65.1, 106.4, 111.4, 117.9, 118.7, 121.1, 126.2, 135.5, 136.2, 171.9; ESIMS (m/z) 301 [M + H]+; HRMS (ESI) calcd for C17H21N2O3 301.1547, found 301.1542; IR (CHCl3) νmax 3500, 3284, 1670, 1628 cm−1. (−)-tert-Butyl (1S,11bS)-1-{2-[(tert-Butoxycarbonyl)oxy]ethyl}11b-{[(tert-butoxycarbonyl)oxy]methyl}-3-oxo-1,2,3,5,6,11b-hexahydro-11H-indolizino(8,7-b)indole-11-carboxylate (13). To a stirred solution of diol (+)-12 (210 mg, 0.70 mmol) in CH2Cl2 was added (Boc)2O (0.535 mL, 2.45 mmol) and a catalytic amount of DMAP (17 mg, 0.14 mmol), and the reaction mixture was stirred at 25 °C for 4 h. Reaction was quenched with water, and aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 60−120 mesh, EtOAc−PE, 15:85) afforded compound (−)-13 as a solid (418 mg, 99%). Mp 72−74 °C; [α]25D −116.3 (c 1.0 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.42 (s, 9H), 1.47 (s, 9H), 1.72 (s, 9H), 1.95 (sept, J = 6.7 Hz, 1H), 2.38 (dd, J = 17.1 and 6.7 Hz, 1H), 2.55−2.80 (m, 4H), 2.93 (sept, J = 6.7 Hz, 1H), 3.37 (td, J = 12.8 and 5.5 Hz, 1H), 4.01−4.10 (m, 1H), 11131

DOI: 10.1021/acs.joc.7b02122 J. Org. Chem. 2017, 82, 11126−11133

Article

The Journal of Organic Chemistry calcd for C34H47N2O9 627.3276, found 627.3268; IR (CHCl3) νmax 1734, 1682 cm−1. 15b: Mp 73−74 °C; [α]25D −111.3 (c 0.1 CHCl3); 1 H NMR (CDCl3, 400 MHz) δ 1.31 (s, 9H), 1.49 (s, 9H), 1.73 (s, 9H), 1.78−1.90 (m, 1H), 2.15 (d, J = 7.3 Hz, 3H), 2.40−2.51 (m, 1H), 2.63 (dd, J = 16.5 and 4.9 Hz, 1H), 3.00 (ddd, J = 16.2, 10.7, and 7.3 Hz, 1H), 3.40 (d, J = 11.6 Hz, 1H), 3.50 (td, J = 11.6 and 5.5 Hz, 1H), 4.02−4.12 (m, 1H), 4.22−4.32 (m, 1H), 4.46 (dd, J = 13.4 and 7.3 Hz, 1H), 4.83 (d, J = 11.6 Hz, 1H), 5.08 (d, J = 11.6 Hz, 1H), 5.82 (q, J = 7.3 Hz, 1H), 7.22 (t, J = 6.7 Hz, 1H), 7.29 (t, J = 7.3 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.6, 20.1, 27.5, 27.8, 28.3, 28.9, 35.3, 42.7, 64.4, 65.0, 67.2, 81.7, 82.0, 84.6, 116.0, 118.4, 118.8, 122.8, 124.9, 128.8, 131.8, 134.8, 135.1, 135.6, 150.2, 153.1, 153.6, 170.1; ESIMS (m/z) 627 [M + H]+; HRMS (ESI) calcd for C34H47N2O9 627.3276, found 627.3266; IR (CHCl3) νmax 1736, 1681 cm−1. (−)-tert-Butyl (1S,11bS,E)-1-{2-[(tert-Butoxycarbonyl)oxy]ethyl}11b-{[(tert-butoxycarbonyl)oxy]methyl}-2-ethylidene-1,2,3,5,6,11bhexahydro-11H-indolizino(8,7-b)indole-11-carboxylate (16). The solution of AlCl3 (42 mg, 0.319 mmol) in THF (5 mL) was added dropwise to a stirred suspension of LAH (35 mg, 0.958 mmol) in THF (15 mL) at 0 °C under argon atmosphere. The reaction mixture was stirred for 30 min, and solution of lactam (−)-15a (100 mg, 0.159 mmol) in THF (10 mL) was added dropwise at 0 °C. The reaction mixture was stirred for 1.5 h at 0 °C, and the reaction was quenched with saturated aqueous Na2SO4 at 0 °C. Reaction mixture was diluted with EtOAc (20 mL), filtered through a Celite pad, and dried over Na2SO4. The organic layer was concentrated in vacuo, and purification of the obtained residue by column chromatography (silica gel, 230− 400 mesh, PE−EtOAc, 25:75) afforded amine (−)-16 as a solid (90 mg, 92%). Mp 67−69 °C; [α]25D −37.4 (c 0.3 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 1.27 (s, 9H), 1.43 (d, J = 6.7 Hz, 3H), 1.48 (s, 9H), 1.73 (s, 9H), 1.85−2.00 (m, 1H), 2.16 (sext, J = 12.8 Hz, 1H), 2.49 (dd, J = 17.1 and 5.5 Hz, 1H), 3.00−3.25 (m, 3H), 3.50−3.60 (m, 1H), 3.69 (d, J = 12.2 Hz, 2H), 4.02 (q, J = 7.9 Hz, 1H), 4.17−4.25 (m, 1H), 4.58 (d, J = 11.0 Hz, 1H), 5.09 (q, J = 7.3 Hz, 1H), 5.24 (d, J = 11.0 Hz, 1H), 7.15−7.30 (m, 2H), 7.44 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 14.0, 15.8, 27.5, 27.8, 27.9, 28.3, 41.0, 43.3, 52.9, 65.4, 67.4, 70.9, 81.37, 81.40, 84.0, 115.8, 117.2, 118.0, 118.3, 122.2, 124.1, 129.3, 135.0, 136.2, 139.1, 150.5, 153.3, 153.7; ESIMS (m/z) 613 [M + H]+; HRMS (ESI) calcd for C34H49N2O8 613.3483, found 613.3481; IR (CHCl3) νmax 1734 cm−1. (+)-2-[(1S,11bS,E)-2-Ethylidene-11b-(hydroxymethyl)2,3,5,6,11,11b-hexahydro-1H-indolizino(8,7-b)indol-1-yl]ethan-1-ol (17). To a stirred solution of compound (−)-16 (75 mg, 0.122 mmol) in CH2Cl2 (5 mL) was added TFA (0.188 mL, 2.44 mmol) at 0 °C. The ice bath was removed after 30 min, and the reaction mixture was further stirred for 12 h at 25 °C. On complete consumption of starting material (by TLC), the reaction was quenched by adding saturated aqueous NaHCO3 at 0 °C. Aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and the combined organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated in vacuo, and the obtained TFA salt of amine was dissolved in DCM (5 mL). The salt was neutralized with 4 N NaOH, and aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic layer was washed with brine and dried over Na2SO4. Concentration of the organic layer in vacuo followed by purification of the obtained residue by column chromatography (silica gel, 230−400 mesh, MeOH−DCM, 10:90) afforded compound (+)-17 as a solid (36 mg, 96%). Mp 186− 187 °C; [α]25D +29.6 (c 0.32 MeOH); 1H NMR (CD3OD, 400 MHz) δ 1.49 (d, J = 6.7 Hz, 3H), 1.85 (sext, J = 6.7 Hz, 1H), 2.10 (sext, J = 6.7 Hz, 1H), 2.53 (dd, J = 15.9 and 5.5 Hz, 1H), 3.00−3.10 (m, 1H), 3.17 (dd, J = 14.0 and 6.1 Hz, 1H), 3.24−3.50 (m, 3H), 3.57−3.77 (m, 3H), 3.87 (d, J = 10.4 Hz, 1H), 4.04 (d, J = 10.4 Hz, 1H), 5.17 (q, J = 7.3 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H); 13C NMR (CD3OD, 125 MHz) δ 14.8, 16.3, 32.5, 43.7, 44.5, 54.1, 61.2, 66.2, 68.3, 107.9, 111.9, 118.2, 118.7, 119.4, 122.0, 128.2, 137.1, 137.8, 140.5; ESIMS (m/z) 313 [M + H]+; HRMS (ESI) calcd for C19H25N2O2 313.1919, found 313.1908; IR (Nujol) νmax 3422, 3267 cm−1.

(+)-(6S,E)-5-Ethylidene-7-methylene-1,4,5,6,7,8-hexahydro-2H3,6-ethanoazonino(5,4-b)indole (Subincanadine E, 18). To a stirred solution of compound (+)-17 (16 mg, 0.051 mmol) in THF (7 mL) was added Et3N (83 μL, 0.614 mmol), DMAP (6.20 mg, 0.051 mmol), and p-TsCl (58 mg, 0.307 mmol) at 0 °C. The reaction mixture was stirred for 6 h and allowed to reach 25 °C. Upon complete consumption of starting material, LiBr (52 mg, 0.614 mmol) was added, and the mixture was refluxed for 3 h. The reaction mixture was allowed to reach 25 °C, and zinc dust (80 mg, 1.228 mmol) was added to the reaction mixture. The reaction mixture was again refluxed for 3 h under argon atmosphere. The reaction mixture was concentrated in vacuo, and to the obtained residue was added a saturated solution of NaHCO3. The reaction mixture was extracted with EtOAc (3 × 10 mL), and the combined organic layer was dried over Na2SO4. Concentration of the organic layer in vacuo followed by column chromatography (silica gel, 230−400 mesh, MeOH−DCM, 10:90) of the obtained residue provided (+)-subincanadine E (18) as a white solid (8 mg, 59%). Mp 143−144 °C; [α]25D +42.3 (c 0.12 MeOH), {lit.1 [α]23D +39.0 (c 1.0 MeOH)}; 1H NMR (CD3OD, 400 MHz) δ 1.75−1.92 (m, 1H), 1.83 (d, J = 6.7 Hz, 3H), 2.41 (sept, J = 7.4 Hz, 1H), 3.11 (td, J = 12.1 and 6.1 Hz, 1H), 3.21 (d, J = 17.7 Hz, 1H), 3.30−3.45 (m, 2H), 3.69 (d, J = 13.4 Hz, 1H), 3.89 (t, J = 15.2 Hz, 1H), 3.97 (d, J = 15.2 Hz, 1H), 4.15−4.30 (m, 2H), 5.57 (s, 1H), 5.59 (s, 1H), 6.09 (q, J = 7.3 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H); 13C NMR (CD3OD, 100 MHz) δ 14.1, 21.0, 26.4, 42.4, 46.9, 53.5, 59.1, 109.3, 112.1, 118.9, 120.6, 120.7, 123.6, 129.1, 129.2, 132.1, 137.0, 137.5, 143.3; ESIMS (m/z) 313 [M + H]+; HRMS (ESI) calcd for C19H23N2 279.1856, found 279.1857; IR (Nujol) 3403 cm−1.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02122. 1 H NMR, 13C NMR, and DEPT spectra of all compounds and HPLC plots of compound (±)-9/ (−)-9 (PDF) X-ray crystallographic data of compound 12 (CIF) X-ray crystallographic data of compound 29 (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Narshinha P. Argade: 0000-0003-4553-4076 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.G.K. thanks CSIR, New Delhi, for the award of a research fellowship. N.P.A. thanks the Science and Engineering Research Board (SERB), New Delhi for financial support.

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REFERENCES

(1) Kobayashi, J.; Sekiguchi, M.; Shimamoto, S.; Shigemori, H.; Ishiyama, H.; Ohsaki, A. J. Org. Chem. 2002, 67, 6449−6455. (2) Ishiyama, H.; Matsumoto, M.; Sekiguchi, M.; Shigemori, H.; Ohsaki, A.; Kobayashi, J. Heterocycles 2005, 66, 651−658. (3) Arens, H.; Borbe, H. O.; Ulbrich, B.; Stöckigt, J. Planta Med. 1982, 46, 210−214. (4) Lim, K.-H.; Low, Y.-Y.; Kam, T.-S. Tetrahedron Lett. 2006, 47, 5037−5039. (5) Wong, S.-P.; Chong, K.-W.; Lim, K.-H.; Lim, S.-H.; Low, Y.-Y.; Kam, T.-S. Org. Lett. 2016, 18, 1618−1621.

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The Journal of Organic Chemistry (6) Liu, Y.; Luo, S.; Fu, X.; Fang, F.; Zhuang, Z.; Xiong, W.; Jia, X.; Zhai, H. Org. Lett. 2006, 8, 115−118. (7) Suzuki, K.; Takayama, H. Org. Lett. 2006, 8, 4605−4608. (8) Gao, P.; Liu, Y.; Zhang, L.; Xu, P.-F; Wang, S.; Lu, Y.; He, M.; Zhai, H. J. Org. Chem. 2006, 71, 9495−9498. (9) Chen, P.; Cao, L.; Li, C. J. Org. Chem. 2009, 74, 7533−7535. (10) Cheng, X.; Duhaime, C. M.; Waters, S. P. J. Org. Chem. 2010, 75, 7026−7028. (11) Chen, P.; Cao, L.; Tian, W.; Wang, X.; Li, C. Chem. Commun. 2010, 46, 8436−8438. (12) Solé, D.; Bennasar, M.-L.; Jiménez, I. Synlett 2010, 6, 944−946. (13) Yu, F.; Cheng, B.; Zhai, H. Org. Lett. 2011, 13, 5782−5783. (14) Tian, J.; Du, Q.; Guo, R.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett. 2014, 16, 3173−3175. (15) Markad, S. B.; Argade, N. P. J. Org. Chem. 2016, 81, 5222−5227. (16) Batwal, R. U.; Argade, N. P. Org. Biomol. Chem. 2015, 13, 11331−11340. (17) Deore, P. S.; Argade, N. P. J. Org. Chem. 2014, 79, 2538−2546. (18) Deore, P. S.; Argade, N. P. Org. Lett. 2013, 15, 5826−5829. (19) Mondal, P.; Argade, N. P. J. Org. Chem. 2013, 78, 6802−6808. (20) Byrd, K. M. Beilstein J. Org. Chem. 2015, 11, 530−562. (21) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817−3856. (22) Liu, H.; Yu, J.; Li, X.; Yan, R.; Xiao, J.-C.; Hong, R. Org. Lett. 2015, 17, 4444−4447. (23) Mondal, P.; Argade, N. P. Synthesis 2014, 46, 2591−2594. (24) The 1H NMR spectrum of formed ∼1:1 mixture of diastereomeric products is included in the Supporting Infomation as Figure S54 (S-57). (25) Ballette, R.; Pérez, M.; Proto, S.; Amat, M.; Bosch, J. Angew. Chem., Int. Ed. 2014, 53, 6202−6205. (26) Wright, S. W.; Choi, C.; Chung, S.; Boscoe, B. P.; Drozda, S. E.; Mousseau, J. J.; Trzupek, J. D. Org. Lett. 2015, 17, 5204−5207. (27) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404−13405.

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